Sequenced Treatment Making Inroads in HER2-Positive Early Breast Cancer

Gina Battaglia, PhD

Published: Wednesday, Aug 02, 2017

Denise Yardley, MD

The introduction of targeted therapies has transformed HER2-positive breast cancer from an aggressive disease with poor outcomes to a highly manageable disease with potential for longterm survival. However, further research is needed to identify subgroups who would benefit from new treatment regimens, according to experts who participated in an OncLive® Peer Exchange® panel.

The panelists discussed the use of dual-targeted and extended adjuvant therapy for patients with early-stage HER2-positive breast cancer; the optimal sequence of chemotherapy, HER2-targeted therapy, and hormonal therapy for patients with HER2-positive, estrogen receptor (ER)–positive, and progesterone receptor–positive (ie, “triple-positive”) breast cancer; and management of patients with brain metastases. The panelists stated that patients at high risk for recurrence will likely benefit from dual and extended targeted therapy, although proactive management of adverse effects, namely diarrhea, is important to ensure tolerability of treatment. Additionally, they stated that sequencing of therapies for hormone receptor (HR)–positive/HER2-positive breast cancer may help minimize the cumulative toxicity while delivering the benefits of a multimodal approach. Finally, the panelists agreed on the urgent need for effective treatment of brain metastases that avoids whole-brain radiation therapy (WBRT).

Adjuvant Therapy for Early-Stage Cancer

Previous studies have shown that dual HER2- targeted therapy with pertuzumab (Perjeta) and trastuzumab (Herceptin) plus docetaxel improves progression-free and overall survival in patients with metastatic HER2-positive breast cancer1 and increases the rate of pathologic complete response (pCR) in patients with locally advanced or early HER2-positive breast cancer in the neoadjuvant setting.2 Recent results from the APHINITY trial3 indicate that adjuvant therapy with pertuzumab, trastuzumab, and chemotherapy may also benefit select patients with HER2-positive early-stage breast cancer, according to the panelists. In the APHINITY trial, patients who received the pertuzumab-containing regimen had an invasive disease-free survival (iDFS) rate of 94.1% at 3-year follow-up versus 93.2% for those who received trastuzumab, chemotherapy, and placebo.

The benefits were particularly notable in patients with node-positive disease, whereas 3-year iDFS was not different between treatment groups in the subgroup with node-negative disease. Thus, the panelists agreed that they would most likely limit use of this treatment regimen in the adjuvant setting for patients with early-stage breast cancer at high risk for recurrence, although further studies are needed. “The discussion is not going to be on whether to use it…but rather in whom to use it,” said José Baselga, MD, PhD.

Denise A. Yardley, MD, also stated that the positive outcomes in the placebo groups indicate that adding pertuzumab may not be necessary for all patients with HER2-positive early breast cancer, who generally have good outcomes with current standards of care. “I think picking out those subgroups that are really most likely to derive the benefit are the ones that I’ll be looking at,” she said.

The panelists noted that although the APHINITY trial showed a higher incidence of severe diarrhea in the pertuzumab group of 9.8% versus 3.7% in the placebo group, concerns about toxicity are minimal. “We have seen a little bit more diarrhea, but it’s self-limited,” said Baselga.

Kimberly L. Blackwell, MD, also pointed out that many factors can contribute to diarrhea, particularly with the TCHP regimen (docetaxel, carboplatin, trastuzumab, and pertuzumab), and that pertuzumab-induced diarrhea may continue for some time after discontinuation due to the long halflife of the drug. “I think you have to just be careful and understand that there are lots of things during this period that can cause diarrhea,” she said.

Extended Adjuvant Therapy for Early-Stage Cancer

The panelists also discussed data supporting neratinib (Nerlynx), a tyrosine kinase inhibitor, for extended adjuvant treatment of patients with earlystage HER2-positive breast cancer. The ExteNET trial4 demonstrated that neratinib given within 2 years of trastuzumab-based chemotherapy led to a higher rate of 2-year iDFS than placebo (94.2% vs 91.9%, respectively). According to Baselga, these results were enough for the FDA’s Oncologic Drug Advisory Committee to recommend FDA approval, even though the different sponsors and multiple amendments to the study protocol increased the complexity of assessing the true benefits of neratinib. On July 16, the FDA approved neratinib in the extended adjuvant setting.